Psychopharmacologically active tetra-, penta-, hexa-, and heptapeptides

ABSTRACT

The invention relates to certain psychopharmacological peptides with the formula:

United States Patent 1 1 Greven t 1451 Dec. 24, 1974 75 Inventor:

[ PSYCHOPHARMACOLOGICALLY ACTIVE TETRA-, PENTA-, HEXA-, AND HEPTAPEPTIDES I Hendrik Marie Greven, Heesch, Netherlands [73] Assignee: Akzonalncorporated,Asheville,

22 Filed: Mar. 2,1973 21 Appl. 5102337 507 [30] I Foreign Application Priority Data Primary Examiner-Lewis Gotts Assistant ExaminerReginald J Suyat Attorney, Agent, or Firm-Francis W. Young; Philip M. Pippenger; Hugo E. Weisberger I57] I ABSTRACT The invention relates to certain psychopharmacological peptides with the formula:

in which A represents:

H :l: H DJ M i ii-.- .L..,.MEL7 .Q H D Met( O H L Med-+0 H-D- Men- 0 desamino Met; d.esamino-Met( (T 15 desamino-Met; desamino-Met( O), desamino-Met 0 or the moiety: H N-BJ-CO; in which B is a branched or unbranched alkylene group with 1-6 carbon atoms,

X represents the group OH or NlH and Y represents the group LPhe-OH, L-Phe--Gly-OH or-a (N-phenyl-alkyl)amino group of the formula R -NH-A1k@ in which Alkrepresents a branched or unbranched alkylene group with l-6 carbon atoms and R represents hydrogen, halogen, hydroxy, a lower alkyl (14 C) or loweralkoxy (l-4 C) group,

as well as to functional derivatives of these peptides.

The above compounds inhibit the extinction of conditioned avoidance response, that means that they can be used, in general, as antidepressant agents. More particularly they can be used for the treatment of mental disorders .whereby a stimulation of the mental performance is desired.

4 Claims, No Drawings '1 w PSYCHOPHARMACOLOGICALLY ACTIVE v TETRA-I PENTA-, HEXA-, AND HEPTAPEPTIDES The invention relates to peptides and peptide derivatives with valuable psychophar'macological activities.

From European Journal of Pharmacology 2, 14 (1967) certain peptide fragments of the natural adrenocortiocotrophic hormones (ACTH) areknown to inhibit the extinction of the conditioned avoidance response. Especially the peptide having the amino acid sequence 1-10 of ACTM proved to be active in this respect. Moreover it was found that the first three amino acids (Ser-Tyr-Ser) could even entirely be omitted without much loss of activity. The article ends with the conclusion that. the peptide with the amino acid sequence 4-10 of ACTH, viz. H-MetGlu-His--- Phe-Arg (or Lys)-TrpGly- OH, is the shortest peptide, and perhaps the key sequence for the said activity.

The. peptide withthe amino acid sequence 4-l0 of ACTH does not only exert the psy chopharm-acological property mentioned above, but also a slight MSH activity, as usual in this type of ACTH fragments. Althoughthe effect ofa low dose administration ofa MSH active peptide in men is still unknown, a search was made for peptides having at least the same psychopharmacological activity, but no or a reduced MSH-activity.

In our co-pending Netherlands Pat. application No. 72,02,278 and corresponding copending U.S. application Ser. No. 331,945,filed Feb 12, 1973, it is already indicated that the N-terminal amino acid L-Met of the 4-10 ACTH peptide can be replaced by the amino acid or acid moieties: DMET, L- or DMet( O), L or DMet O desaminoMet, desamino-Met O), desamino-Met '0 or the group H2N-B(l3,

in which B representsa branched or unbranched alkylene group with 1-6 carbon atoms, such as glycyl, valyl, alanyl, B-alanyl or ((X-.-MC) Alanyl, without any loss of activity. The modification, (from L-Met) into DMet, methionylsufoxide, methionylsulfone, desamino-methionyl, desamino-methionylsulfoxide, desamino-methionylsulfone and fl alanyl .even increases the said psychopharmacological activity.

Surprisingly it has now been found that a replacement of the C-terminal peptide residue Trp- GlyOH" of the original peptide: 4-l0 ACTH by L-- Phe-OH, LPhe-Gly--OH, or a (N- phenylalkyl)amino moiety, causes a considerableincrease of the inhibition of the extinction of the conditioned avoidance response, in comparison with 4-10 ACTH. v

The present invention therefore comprises the manu facture and use of peptides and peptide derivatives of the general formula:

L-Lys)Y, v in which A represents: HL- or D-Met, H-L- or DMet( O),

Y represents: the group L-Phe-OH, LPhe-- GlyOH or an (N-phenylalkyl)amino group of the formula:

in which Alk represents a branched or unbranched alkylene group with [-6 carbon atoms, and R represents hydrogen, halogen, hydroxy, or a lower alkyl or alkoxy group, the alkyl group contains 14 carbon atoms, as well as the functional derivatives thereof.

By replacing the C-terminal peptide residue Trp--- GlyOH of the original 4-10 ACTH peptide by the groupings represented by Y" the psychopharmacological activity obtained is roughly about three times stronger. This activity can be raised further by replacing the N-terminal amino acidresidue L-Met (of the original 4-10 ACTH peptide) by another suitable moiety, in particular, BAla, DMet, L or DMet( O), L or DMet( 0 desamino-Met or the corresponding sulfoxide or sulfone.

The peptides and peptide derivatives according to the invention are prepared by a process commonly used in peptide chemistry. The processes that are employed usually for the manufacture of the present compounds .can be summarized as follows:

a. condensation of acompound (amino acid, peptide) having a free carboxyl group and protected other reactive groups, with a compound (amino acid, peptide or amine) having a free amino group and protected other reactive groups, in the presence of a condensationagent;

b. condensation of a compound (amino acid, peptide) having an activated carboxyl group and optionally protected other reactive groups, with a compound (amino acid, peptide, amine) having a free NH, group and optionally protected other reactive groups;

c. condensation of a compound (amino acid, peptide) having a free carboxyl group and optionally protected other reactive groups, with a compound (amino acid, peptide, amine) having an activated amino group and optionally protected other reactive groups, after which the protecting groups are removed, if necessary.

Activation of the carboxyl group can be effected, for example, by converting the carboxyl group into an acid halide, an azide, anhydride, imidlazolide, or an activated ester such as the N-hydroxy-succinimido ester, or the p-nitro-phenyl ester;

The amino group can be activated by converting it into a phosphite amide or by the phosphor-azo" method.

Methods usually employed for the above condensation reactions are: the carbodiimide method, the azide method, the mixed anhydride method and the method of the activated esters as described in The Peptides] vol. I, 1965 (Acad. Press), by E. SchriSder and K. Liibke. Moreover Merrifields so-called Solid Phase method, described in J. Am. Chem. Soc. 85, 2149 (1963), can be applied for the manufacture of the present peptides and peptide derivatives. I

The reactive groups .that are not'allowed to participate in the condensation reaction are protected effectively by the so-called protecting groups, which can be easily removed again, for example, by hydrolysis or reduction. Thus, for example, a carboxyl group can be protected effectively by esterification with methanol, ethanol, tertiary butanol, benzylalcohol or pnitrobenzylalcohol, or by conversion into an amide.

This latter protecting group is very hard to remove, however. so that it is recommendable to use this group only to protect the carbox yl group of the C-terminal amino acid in the ultimate peptide or the Y-carboxyl group of glutamic acid. In this case the peptide synthesis leads direct to the amide of a peptide according to formula I.

Groups that are capable of protecting an amino group effectively are usually acid groups, for example an acid group derived from an aliphatic, aromatic, araliphatic or heterocyclic carboxylic acid, such as acetic acid, benzoic acid, or pyridine-carboxylic acid, or an acid group derived from carbonic acid such as the group ethoxy-carbonyl, benzyloxy-carbonyl, tbutyloxy-carbonyl or p-methyloxy-benzyloxy-carbonyl, or an acid group derived from a sulfonic acid, such as the group benzene-sulfonyl or p-toluene-sulfonyl, but also other groups can be employed, such as substituted or unsubstituted aryl or aralkyl groups, for example benzyl and triphenylmethyl, or groups such as ortho-nitro-phenyl-sulfenyl and 2-benzoyl-lmethylvinyl.

It is mostly recommendable also to protect the guanidine group of arginine, the e-amino group of lysine, and the imidazole group of histidine. but this protection is not absolutely necessary. Conventional protecting groups in this connection are a tertiary butyloxycarbonyl, or a tosyl group for the e-amino group of lysine, a nitro group for the guanidine group of arginine, and a benzyl, dinitro-phenyl or a trityl group for the imidazole group of histidine.

The protecting groups can be split off by various conventional methods, depending upon the nature of the group in question, for example with trifluoro acetic acid, or by mild reduction, for example with hydrogen and a catalyst, such as palladium, or with HBr in glacial acetic acid.

Peptides according to the present invention having as the N-terminal moiety a methionylsulfoxide or desaminomethionylsulfoxide group, may be prepared from the corresponding Metor Desamino-Met peptide by means ofa mild oxidation known per se, for example with dilute hydrogenperoxide or a peracid. Such as oxidation yields a mixture of the S- and R-sulfoxide (=d or l-sulfoxide), which mixture may be split off into the separate diastereomeric compounds in a conventional manner.

By coupling the S- or R-sulfoxide dor 1- sulfoxide) or methionine or desaminomethionine with the peptide H-Glu (X)HisPheArg(or Lys)Y, in which X and Y have the meanings indicated above, the separate enantiomers can also be obtained in a direct way.

The peptides according to the invention having as the N-terminal residue a methionylsulfone (Met or desaminomethionylsulfone (desamino-Met- 0 group may be prepared most conveniently by an oxidation known per se of the corresponding Metor Desamino-Met peptide, for example with 1-1 0 or a peracid.

By functional derivatives of the peptides and peptidederivatives according to the invention are meant:

1. the pharmaceutically acceptable acid addition salts of the peptides and peptide derivatives,

2. peptides or peptide derivatives in which one or more free amino groups have been substituted by an acyl group derived from an aliphatic carboxylic acid with l6 carbon atoms, such as 6 acetyl group;.

3. unsubstituted amides or lower alkyl (1-6 C) substituted amides of those peptides and peptide derivatives according to the invention having a free carboxyl group, such as a N(CH or N(C H group.

4. esters of the present peptides derived from aliphatic or araliphatic alcohols with 1-18 carbon atoms; in particular, the lower aliphatic (1-6 C) alcohols, such as methanol, ethanol. butanol, pentanol or cyclohexanol, and the lower araliphatic (7-10 C) alcohols. such as benzylalcohol, phenylethylalcohol. phenylpropylalcohol, or cinnamylalcohol,

5. metal complexes formed by contacting the peptides or peptide derivatives with a sparingly soluble salt. hydroxide or oxide of a metal, preferably zinc, or preparations obtained by associating the present peptides with organic, mostly polymeric, compounds, such as gelatine, polyphloretinphosphate or polyglutamic acid, to obtain a prolonged mode of action.

The acid addition salts are obtained by reacting the present compounds with a pharmaceutically acceptable organic or inorganic acid, such as HCl, phosphoric acid, acetic acid, maleic acid, tartaric acid or citric acid.

As already briefly said the present peptides and peptide derivatives as well as their functional derivatives defined above have valuable psychopharmacological activities. The present compounds inhibit the extinction of conditioned avoidance response, that means that they can be used, in general, as antidepressant agents. More particularly they can be used for the treatment of certain mental disorders whereby a stimulation of the mental performance is desired, such as in certain types of neurosis and in old-age infirmities (senility).

The peptides according to the invention and the functional derivatives defined above can be administered orally, parenterally or intranasally. Preferably the peptides are employed as an injection preparation, for

' which purpose they are dissolved, suspended or emulsified in a suitable liquid, but mixed with suitable auxiliaries and fillers they can also be placed in a form suitable for oral administration, such as pills, tablets or coated tablets. The present peptides can also be administered in the form of suppositories or sprays.

The peptides or peptide derivatives according to the invention are preferably administered in daily dosages of from 0.001 to 1 mg per kg body weight. dependent upon the peptids activity level and the form in which they are administered.

Exceedingly valuable preparations are obtained if the present peptides are placed in a form in which they have a prolonged activity, for example, incorporated into gelatin, polyphloretinphosphate or polyglutamic acid, or preferably as metal complexes. These metal complexes can be obtained by contacting the peptides with sparingly soluble metal salts, metal hydroxides or metal oxides. As sparingly soluble metal salts the metal phosphates, metal pyrophosphates and metal polyphosphates are commonly used.

Metals than can be used in this process are the metals belonging to the b-groups of the periodic system, for example cobalt, nickel, copper, iron, and preferably zinc, as well as the metals belonging to the main groups of the periodic system and capable of forming complexes, such as magnesium and aluminum. The prepa 5 6 ration of the said metal complexes takes place in the Z j y yy conventional manner. P

Thus, for example, a metal complex can be obtained Me a methyl y by adding the peptide and a poorly soluble metal salt, g f P'q'i l f m'etal hydroxide or metal oxide to an aqueous medium. u 0 The metal complex can also be obtained by adding an III. For he lv t 5 alkaline medium to an aqueous solution of the peptide viations i f g z g reagents the following dbbre and an insoluble metal salt to form the insoluble peptide/metal hydroxide complex.

Moreover, the metal complex can be obtained by 1 =bcnzunc adding the peptide, a soluble metal salt and a soluble EIOH ethanol salt to an aqueous, preferably alkaline medium to form E; l an insoluble peptide/metal salt complex in situ. Ac or HAc acetic acid The metal complexes can be employed at once as if z z l' i ll CO suspensions, or for example be lyophilized and afteriPro isogropanol ards uspended again ?}I:I/IFF dimcthylformuniidc I i tetrahydrofurain Biological activity. Extinction of the conditioned avoid- DCCI dicycmhcxyl carhodiimidc H1106 response. CHU dicyclohexyl-ureii 1 AA iriethylzimine Ma e wh te rats weighing approximately 150 grams TFA trmumo acetic acid were conditioned by means of the so-called polewt! \vuler umping test. The conditioned stimulus was a light presented over the cage for 5 seconds, whereupon the un- I For the amino acid residues the following conditioned stimulus of shock was delivered through abbreviations have been used: the grid floor of the cage.

For 3 consecutive days 10 tests were run every day with an average interval of 60 seconds. The day after i mmhmyl Meti O) methionylsulloxidc (race) this acquisition period the extinction was studied in ses- Met(d, 0) mcthionyKdlsulfoxide sions of 10 trials. All animals that made 8 or more posi- O) i t.v th f, t Met(- 02) niethionylsulfonc i e responses in e irs extinction sess on were G|u(X) g|uwmy| (X OH) treated with the substance to be tested or with a pla- 00 glutaminyl (X NHZ) Gln cebo. After that, extinction sessions of 10 trials each H11; Qgiffji' were carried out 2 and 4 hours after the treatment of e ursinyl the animals with the substance to be tested. :2

In the following table the results of the known pep- Val va lyi tide 410 ACTH are compared with some peptides ac- 2 2' I a a ll any cording to this invention. a. e)A]; wmcthylalanyl Dosage Estimated in ugm First Second Third potency Peptide per session session session ratio animal after after compared sc. 0 hour 2 hours 4 hours wiih 4-10 ACTH l) H-Met-- Glu-HisPhe Arg-Trp-Gly-OH 100 8 8 7 (4-10 ACTH) 30 8 5 3 i HMet- 30 8 8 7 GluHis-Phe- Arg- PheG|yOl-l l0 8 5 4 3 HMet( 0) l0 9 9 7 GluHis- Phe-Arg- Phe-- 3 9 9 4 10 Gly-OH BA|a-- 30 9 9 s Glu-His-Phe- Lys-PhcOH l0 s s 7 3 9 6 4 l0 H-Met-- 3o 9 9 s G|u-His-Phe l. If no optical confi form is meant.

II. The following abbreviations have been used for the protecting or activating groups:

V. Abbreviations used for other residues:

guration has been stated the L- PPA PEA HPEA Amf N-phenylpropylliimino group N-phenylelhyl)amino group N-phydroxyphenylethyl)amino group N-l-phenylisopropyl)amino group d rived from amfetaminc) ll ll ll ll Desamino-Met Preparation starting substances A. Preparatin Boc.MetGlu(OtBu)HisN H;, 1. BocMetGlu(OtBu)HisOMe Boc-Met-MH (10.52 g), dissolved in 75 ml of DMF, is cooled down to C, after which 23.6 ml of 3.4

N HCl in THF are added, and at -20C 5.85 ml (43.3

mmol) of isoamyl nitrite. The mixture is stirred for 7 minutes at 20C and then added to a solution of 17.05

g of HGlu(OtBu)l-lisOMe.2 HCl in 50 ml of dimethylformamide. Then enough triethylamine is added to adjust the final pH of the mixture to 6.9. Then the mixture is stirred for 3 days at 0C. The triethylaminel-lCl formed is then filtered off and the filtrate evaporated to dryness. The residue is dissolved in 150 ml of ethyl acetate/water. The water layer is separated and the ethyl acetate layer washed twice with water. Then the water layers are combined and extracted again with ethyl acetate (2 X 25 ml). The ethyl acetate layers are dried, after which the solution is evaporated to about 100 ml and set aside at 0C.

Melting point: 138l42C.

Rf in BuzAc1Wa (4:111) 0.59 on SiO Of the above methyl ester 3.7 g are dissolved in 70 ml of methanol, after which 3.7 ml of hydrazine hydrate are added. The mixture is stirred for 5 hours at room temperature. The solution is evaporated to dryness and then stirred with water and dried.

Rf in AmziProzWa (101415) 0.39 on SiO B. Preparation of Bu)His-N H l. BocD-MetGlu(OtBu)His-OMe Boc-DMetN l-l (10.52 g), dissolved in 75 ml of DMF, is cooled down to 0C, after which 23.6 ml of 3.4 N hydrochloric acid in THF and, at 20C, 5.85 ml of isoamyl nitrite are added. The mixture is stirred for 7 minutes, after which 17.05 g of HGlu (Ot- Bu)His-OMe.2 HCl in 50 ml ofDMF are added and the pH is adjusted to 6.9 with triethylamine. The mixture is stirred for 3 days at 0 and filtered, and the filtrate evaporated to dryness in vacuum. The residue is taken up in 150 ml of ethyl acetate/water and washed with water. The organic phase is dried, after which it is evaporated to 100 ml and set aside at 0. The crystals obtained are dried.

Rf in Bu1Ac1Wa (41111) 0.63 on SiO Melting point: 6971C.

Of the above methyl ester 3.2 g (5.45 mmol) are dissolved in 60 ml of methanol, after which 3.7 m1 of hydrazine hydrate are added. The mixture is stirred for 5 hours at room temperature, after which the methanol is distilled off in vacuum and the residue stirred with water. After being dried, the hydrazide is immediately processed further.

Rf in AmziProzWa (101415) 0.37 (SiO C. Preparation of BocValGlu(OtBu)HisN l-l 1. BocValGlu(OtBu)His-OMe BocVal-OH (3.26 g; mmol) is dissolved in ml of methylene chloride, after which 1.73 g of N- hydroxy-succinimide are added. The mixture is cooled down to 20C. after which 3.09 g of DCCI, dissolved in 20 ml of cooled methylene chloride. are added and the resulting solution is stirred for 1 hour at 20C and then for 20 hours at +20C.

The resulting DCHU is filtered, after which the filtrate is evaporated to dryness and the residue dissolved.

in 30 ml of DMF. Then 7.33 g of Z-Glu(OtBu)-His- OMe, prepared according to Kappler Helv. 44. 1991, 1961 and 1.4 g of 10% palladium/charcoal are added. Then hydrogen is bubbled through the solution for 5 hours, after which the solution is stirred for 1 night, filtered and the filtrate evaporated to dryness.

The residue is dissolved in aqueous ethyl acetate and washed with water, sodium bicarbonate and water. The

organic phase is dried, after which the ethyl acetate is evaporated in vacuum. The residue is recrystallised from ethyl acetate/petroleum ether.

yield: 3.95 g; melting point: 117-119C.

Rf in BzzEtOH (8:2) 0.55 (SiO Of the above methyl ester 3.73 g are dissolved in ml of methanol, after which 3.72 g of hydrazine hydrate are added. The mixture is stirred for 7 hours at room temperature, after which the solution is evaporated to dryness Rf the residue triturated with ether. Rf in AMsi- ProzWa (10:4:5) 0.33 on SiO D. Preparation of BocBAlaGlu(Ot- Bu)HisN H;,

BocBAla-OH (3.78 g) is dissolved in methyl-- ene chloride. The solution is cooled down to 0C, after which 2.3 g of N-hydroxy-succinimide are added. The mixture is cooled down further to -22C, after which 4.12 g of DCCl are added. The mixture is stirred for 30 minutes at 22C, for 3 hours at 0C and for 12 hours at room temperature. The precipitate formed (DCHU) is filtered off, the filtrate evaporated to dryness and the residue taken up in dimethylformamide. To this mixture 9.77 g of zGlu(OtBu)-HisOMe are added and also 1.5 g of palladium (10%) on charcoal as a catalyst. Then hydrogen gas is bubbled through the mixture for 6 hours. Then the mixture is stirred for 12 hours. Then the catalyst is filtered off and the filtrate evaporated to dryness. The residue is taken up in ethyl acetate and the solution washed successively with a so dium bicarbonate solution (5%) and water. The ethyl acetate phase is dried, after which the solution is evaporated to dryness and the residue recrystallised from ethyl acetate/petroleum ether (111).

Melting point: 9395C.

Rf in Bz1EtOl-l (812) 0.25 on SiO The methyl ester obtained in (1) (3 g) is dissolved in 60 m1 of methanol, after which 3 ml of hydrazine hydrate are added. The mixture is stirred for 6.5 hours at room temperature, after which the solution is evaporated to dryness and the residue triturated with dry ether. The substance was immediately used for further reactions.

Rf in AmziProzWa (101415) 0.42 on SiO E. Preparation of BocGly-Glu(OtBu)HisN H 1n the same manner as described in (C.1) Boc-- GlyGlu(OtBu)HisOMe is prepared by reacting Boc-GlyOH with HGlu(OtBu)His-OMe. Melting point: l03-108C.

Rf in Bz1EtOH (812) 0.43 on SiO By reacting this substance with hydrazine hydrate as described in (A2) 1 the BocGlyGlu(Ot Bu)-His-N H is prepared.

Rf in AMziProzWa (10:4:5) 0.32 on SiO F. Prepared in the same manner as described in C. and D.

Rf= 0.33 (AmziProtWa =10:4:5)

Rf= 0.31 (Am:iPro:Wa 10:4:5).

3. DesaminoMet-Glu(OtBu)HisN 11 Rf 0.32 (Am:iPro:Wa 101415). G. Preparation of Boc-Met-Gln-His-MH 1n the same manner as described in (C1) the amino acid derivative Boc-Met-OH is coupled to l-1-Gln-His-OMe, obtained from the corresponding Z- protected peptide (Helv. 44, 476, 1961) by hydrogenation with 10% palladium on charcoal, yielding the pro tected peptide ester: BcMet-GlnHis-OMe, which peptide is immediately processed into the corresponding hydrazide by the method described in C2).

Rf in Am:iPro:Wa (:4:5) 0.28 on SiO H. Preparation of H-Phe-Arg-Phe-Gly-OH.l-1Ac To a solution of 14.5 g of Boc-Phe-OH in 135 ml of methylene chloride are added 9.93 g of 11-- GlyOBzl.HCl, while stirring. The suspension is cooled to 5C, after which 7.1 ml of triethyl amine are added. The mixture is stirred for 5 minutes, after which enough triethyl amine is added to adjust the pH of the mixture to 7-7.2 (about 3 ml). Then the temperature of the mixture is reduced to 22C, after which 10.1 g (49.3 mmol) DCCl in 55 ml of methylene chloride are added. The mixture is stirred for 1 hour at C and for 12 hours at room temperature, after which it is left.

.ane and 45 ml of methylene chloride. After that 54 ml of 5.66 N HCl in ethyl acetate are added at room temperature. Then the mixture is stirred and evaporated to half of the volume, after which dry ether (about 250 ml) is gently added. The resulting white oil is separated from the liquid layer. Then the oil is stirred with ether.

Of the above oil 10.03 g are dissolved in 100 m1 of dioxane, after which successively 4.3 ml of triethyl amine, 2.21 ml of glacial acetic acid and 9.75 g of tbutyloxycarbonyl-(nitro)arginine-acetoxim are added. The mixture is stirred for 40 hours at room temperature, after which it is evaporated to dryness in vacuum. The residue is then taken up in 150 ml of ethyl acetate and washed successively with 0.1 N HCl, water, a sodium bicarbonate solution (5%), water and a saturated NaCl solution. The organic layer is dried and evaporated, and the residue recrystallised from dioxane.

Melting point: about 66C (transition into a thick oil).

Rf in Bz:Et()l-l (9:1 0.35 on SiO 4. H-Arg(NOQ-Phe-Gly-OBZLHCI Of the peptide obtained in (3) 12.5 g are dissolved in 85 ml of ethyl acetate and 40 ml ofnitromethane. Then 35.5 ml of 5.7 N HCl in ethyl acetate are added, after which the mixture is treated as described in (2).

Rf in AmzPyzWa (513:2) 0.66 on SiO To a solution of 9. 14 g of the peptide obtained in (4) in 35 ml of dimethylformamide 3.42 ml of triethyl amine are added at 0C, after which the solution is cooled down to 20C. This solution is immediately added to a solution of 6.8 g of BocPhe-ONP in ml of dimethylformamide, also cooled down to 20C. Then the mixture is stirred for 1 hour at -20C and for 20 hours at room temperature. The excess of active ester is then removed by stirring for 2 hours in the presence of 147 mg of 2-dimethyl aminoethyl amine. The solvent is removed in vacuum. The oily residue obtained is taken up in a mixture of ethyl acetate (200 ml) and water (35 ml). The ethyl acetate layer is washed successively with 0.1 N HCl, water, a potassium carbonate solution (5%), water and a saturated NaCl solution. The solid substance formed during the whole process is collected and dried in vacuum. The ethyl acetate layer is completed with ether to a volume of about 1 litre whereby additional solid substances crystallize out.

Melting point: 175-177C.

Rf in BzzEtOl-l (9:1 0.32 on SiO Of the protected peptide-ester obtained in (5) 10.4 g are dissolved, while stirring, in 36 m1 of 90% trifluoroacetic acid (TFA), cooled down beforehand to about 10C. The reaction mixture was stirred for 1.5 hours and then added to 400 ml of ether, while stirring vigorously. After 2.5 hours the resultingjelly-like white substance is filtered off in vacuum and washed with ether.

7. HPhe-ArgPheGly-OH.acetate Of the peptide obtained in (6) 9.9 g are dissolved in 500 ml of 90% acetic acid. Then 1.8 g of 10% palladium/charcoal are added to this solution. after which hydrogen is bubbled through for 48 hours, while stirring. The catalyst is filtered off and washed with glacial acetic acid. The filtrate is evaporated to dryness in vacuum to obtain a colourless oil, which crystallizes out at 0C after standing under ether for 24 hours.

Rf in Bu:Py:Ac:Wa (4:3/421/411) 0.27 on SiO K. Preparation of HPheLys(Boc)-(N phenylpropyl)amide Z-Lys(Boc)-ONP (10.33 g; 20.6 mmol) is dissolved in ml of methylene chloride at about 0C. Then 2.7 g of 3-phenylpropylamine are added to this solution, after which the mixture is stirred for 1.5 hours at 0C and for 18 hours at room temperature. The solvent is evaporated and the residue dissolved in 200 ml of ethyl acetate. The ethyl acetate solution is washed successively with a sodium carbonate solution (10% a NaCl solution (30%), 0.1 N HCl and a 30% NaCl solution. Then the ethyl acetate layer is dried and evaporated to a volume of about 80 ml. Then enough ether is added to cause a turbidity, after which the mixture is stored in a refrigerator. After 2 hours the precipitate formed is filtered off.

Melting point: 7879C.

Rf in BzzEtOH (9:1) 0.53 on SiO Of the compound obtained in (l) 8.75 g are dissolved in 120 ml of methanol to which 1.2 g of 10% palladium/charcoal are added. While stirring, hydrogen is bubbled through the solution for 3.5 hours, after which the catalyst is filtered off. The filtrate is evaporated to dryness to obtain a practically colourless oil, which is used at once for further reactions.

Rf in AmzFozWa (7:2:1) 0.58 on SiO Of the protected amino acid derivative obtained in (2) 6.39 g are dissolved in 68 ml of dimethylformamide after which a solution of 7.61 g of ZPheONP in 20 ml of dimethylformamide is added. The mixture is stirred at room temperature for 20 hours, after which the solvent is evaporated in vacuum. The residue is dissolved in 170 ml of ethyl acetate and washed successively with a potassium carbonate solution a NaCl solution (30%), 0.1 N HCl and a NaCl solution (30%). The ethyl acetate layer is then dried on Na SO and evaporated to about 100 ml. The solution is stored in a refrigerator for 3 days, during which time the peptide crystallizes out completely.

Melting point: 134136C.

Rf in BzzEtOH (8.2) 0.72 on SiO Of the peptide derivative obtained in (3) 9.07 g are dissolved in 300 ml of dimethylformamide to which 4 ml of 4N HCl and 1.5 g of palladium/charcoal have been added. Hydrogen is bubbled through the so lution for 3.5 hours, while stirring, after which the catalyst is filtered off and the filtrate evaporated to dryness to a practically colourless oil.

Rf in Bu:Ac:Wa (4:121) 0.63 on SiO L. In the same manner as described in example K are prepared:

1. l-lPheLys(Boc)-Amf (the starting amine in this synthesis is L-amfetamine) Rf in BuzAczWa (4:1:1) 0.60 on SiO 2. HPhe-Lys(Boc)PEA (the starting amine is phenylethylamine) Rf in BuzAczWa (4:121) 0.65 on SiO 3. HPheLys(Boc)-HPEA (the starting amine is p-hydroxyphenylethylamine) Rf 0.57. M. Preparation of l-lPheLys(Boc)-Phe derivatlves l-lLys(Boc)-Phe-OMe (4.24 g) is dissolved in 25 ml of dimethylformamide, after which 4.77 g (11.4 mmol) of Z-Phe-ONP are added to this solution. The mixture is stirred for about 24 hours, after which the solvent is evaporated in vacuum. The residue is dissolved in a mixture of 120 ml of ethyl acetate and 30 ml of water, after with the ethyl acetate phase is washed successively with 0.1 N HCl, water, a sodium carbonate solution (5%) and water. The ethyl acetate is distilled off and the residue recrystallised from ethyl acetate to which a little petroleum ether has been added.

Rf in BzzEtOh (8:2) 0.76 on SiO;.

of the peptide obtained in (1) 1.9 g are dissolved in 50 ml of methanol to which 0.5 g of 10% palladium/- charcoal is added. Then hydrogen gas is bubbled through the solution for 3 hours, after which the catalyst is filtered off and the filtrate evaporated to dryness.

Rf in BzzEtOH (8:2) 2 0.35 on SiO Of the ester obtained in (1 500 mg are dissolved in methanol, after which the solution is saturated with ammonia. The mixture is stirred for 24 hours. The Z- protected peptide amide crystallizes from the solution.

In the manner described in (2) the protecting Z- group is removed from this amide.

Rf in BzzEtOl-l (8:2) 0.23 on SiO Of the peptide ester obtained in (2) 0.5 g is dissolved in 6 ml of methanol, after which 1 equiv. of NaOH is added. The mixture is stirred for 1 hour, after which it is gently acidified to precipitate the tripeptide acid.

Rf in BzzEtOH (8:2) 0.18 on $10 1 g of ZPheLys(Boc)PheOH, obtained by saponification of the corresponding methylester de' scribed in (1) by the method described in (4) is dissolved in 15 ml DMF after which 1.1 equiv. phenylpropylbromide and 1.1 equiv. dicyclohexylamine is added to that solution. After two days of stirring the suspension obtained is cooled to 0C and filtered off. The filtrate is evaporated after which aqueous ethyl acetate is added to the residue. The mixture is then washed with 0.1 n HCl, water, 5% sodium bicarbonate and water, whereupon the ethyl acetate phase is dried and evaporated. The residue obtained is partially deprotected (removal of the Z-group) by means of the method described in 2).

Rf in BzzEtOl-l (8:2) 0.40 on SiO N. l-lPheArgPhe derivatives ZPheONP (2.1 g), dissolved in 25 ml of DMF, is added to a solution of 2.3 g of H-Arg(NO PheOMe.HBr, (melting point: 163 dec.) cooled down to 0 and 0.73 ml of triethyl amine. The reaction mixture is stirred for 2 hours at 0 and for 20 hours at 20C, after which it is evaporated and the filtrate stirred three times with dry ether. The residue is recrys tallised from methanol-ether (2:1).

Rf in BzzEtOH (8:2) 0.68 on SiO To a solution of 0.8 g of tripeptide ester of 1) in 30 ml of methanol at about 0C is added dry ammonia (saturated solution) or about 10 equiv. dimethylamine.

After 20 hours stirring at 0C, the temperature is allowed to rise to room temperature. After stirring forl hour the resulting suspension is filtered. Rf in BzzEtOH (8:2) 0.53 on SiO for the unsubstituted amide.

Rf in BzzEtOl-l (8:2) 0.62 on SiO for the dimethylamide.

Of the tripeptide ester of 1) 1.28 g are suspended in 2 ml of 1 N sodium hydroxide and 10 ml of methanol. When a clear solution is obtained, this solution is stirred for another 15 minutes, after which it is acidified with hydrochloric acid to pH 3. The resulting precipitate is filtered and washed with water.

Rf in BzzEtOH (8:2) 0.43 on SiO 4. Deprotection Of the tripeptides 1, 2 or 3 0.5 g is dissolved in 25 ml of acetic acid. Then 10% palladium on charcoal is added, after which the mixture is hydrogenated for 2 days. The resulting black suspension is filtered off,

after which the filtrateis evaporated to a dryness in a vacuum and the residue taken up in water.

The filtrate is filtered again, after which it is lyophilised.

1. Rf* 0.25 on SiO H-Phe-ArgPheOMe- .acetate 2 Rf* 0.18 on SiO,

P. H-PheLys(Boc)--Phe-Gly derivatives Twelve grams of Z-Phe-Lys(Boc)OMe are dissolved in 30 ml of methanol and 6ml of hydrazine hydrate. The solution is left to stand for 24 hours, after which it is stirred at C for 2 hours. The resulting precipitate is filtered off, washed with cold methanol and dried.

Rf in Bz:EtOH (8:2) 0.12 on SiO Ofthe above hydrazide 5.42 g are dissolved in 20 ml of DMF. The solution is cooled down to 0, after which 2 equiv. of hydrochloric acid/THF are added and the mixture is cooled down to 20C. Then 1.35 ml iso isoamyl nitrite are added, after which the mixture is stirred for 7 minutes at 20C and added to a solution of 3.5 g of HPheG1yOBz1.HC1 (H.2) and 4.2 m1 of triethyl amine (pH7). The mixture isleft to stand for 70 hours at 0, after which the solvent is distilled off and the residue taken up in ethyl acetate/water. Then the organic phase is washed with 0.1 N HCl, sodium bicarbonate and water. The ethyl acetate layer is dried over sodium sulphate, after which the ethyl acetate is distilled off in vacuum.

Rf in BzzEtOH (8:2) =0.71 (SiO,).

One gram of the peptide obtained in (2) is dissolved in methanol/water 1:1 (20 ml). Then 10% palladium on charcoal is added, after which hydrogen is bubbled through the mixture for 5 hours. The mixture is filtered over hyflo, after which the filtrate is evaporated and the residue stirred into dry ether.

Rf in BuzAczWa (4:111) 0.43 (SiO EXAMPLE 1 Preparation of H-Met-GluHisPhe-Arg-- Phe-Gly-OH A. Boc-Met-Glu(OtBu)HisPhe-Arg-- triethyl amine till pH 7, are added. By adding extra triethyl amine the pH ofthe whole reaction mixture is adjusted to 7. The mixture is stirred for 30 minutes at 20C, after which it is stored in a refrigerator. At set times, the pH is measured and adjusted to 7, if required. After 48 hours the precipitate formed (triethyl ammonium chloride) is filtered off and the filtrate evaporated to dryness in vacuum. The residue is taken up in 450 ml of ethyl acetate. The mixture is cooled down, after which greyish-white: material crystallizes out, which is removed by centrifugation and successively washed with ethyl acetate, ether. 0.07 N HCl and water, and finally dried.

Rf in Bu:Py:Ac:Wa (4:O.75:0.25:1) I 0.41 on SiO Of the protected heptapeptide obtained in (A) 3.71

g (3.42 mmol) are dissolved in'4 0 ml of trifluoro acetic acid and stirred for 2 hours at room temperature. Then the mixture is poured, while stirring ring, into 350 ml of ether. After 1 hours stirring the white precipitate formed is filtered off and washed with ether. After being dried. the substance is dissolved in a mixture of butanol and water (1:1). after which about 2 g of Dowex X 8 ionexchanger in the acetate form are added. Then the mixture is stirred] for 30 minutes, after which again 2 g of Dowex are added. Then the ionexchanger is filtered off and the filtrate lyophilised.

Rf in Bu:Py:Ac:Wa (2:0.75:0.25:1) 0.30 on SiO Finally the product obtained is subjected to a purification according tothe counter current principle. System Bu:Ac:Wa 4:1:5. Amino acid composition:

His 1.04

Arg 1.00

Glu 1.00

Gly 1.00

Met 0.98

Phe 1.99

EXAMPLE lll AGlu-His-PheArg-Phe- Preparation of Gly-peptides Condensation of the peptide H-Phe-Arg-Phe Gly-OH.HAc, described in H.7, with one of the peptides mentioned in 8.2, C.2, D.2., F.2 and F.3 by the process described in example 1 yields after removal of the protecting group(s) the following peptide acetates:

EXAMPLE 111 I A-Glu-IIis-PhaLys-Phe-Gly-peptides (A Met, Desamino-Met or Gly; X OH or NH l. BocMet-Glu(OtBu)l-lisPheLys(Boc)- PheGly-OH 2.1 of Boc'MetGlu(Ot- Bu)-Hi sN H (see A.2) are dissolved and converted into the azide with isoamyl nitrite by the process described in example I A) and then condensed with HPhe-Lys(Boc)PheGlyOl-l (P.3). The reaction mixture obtained is stirred for 70 hours at 0C and then poured into water, after which the precipitate formed is dissolved in ethylacetate/ethanol (lzl). This solution is slowly added to ether. The precipitate is filtered off.

Rf in Bu:Py:Ac:Wa (4:3/4:l/4:l) 0.54 on SiO 2. In the same manner are obtained:

a. Boc-DMetGlu(OtBu)His-Phe-Lys(- Boc)-PheGly-OH by condensation of the peptide B.2 with the peptide P.3;

b. Desamino-Met-Glu(OtBu)HisPhe-Lys(- Boc)PheGly-OH by condensation of the peptide P3 with the peptide P.3;

c. Boc Met-GlnHisPheLys(Boc)Phe- Gly-OH by condensation of peptide G with the peptide obtained in P.3;

d. Boc-Gly-Glu(OtBu)HisPheLys(Boc)- Phe-Gly-OH by condensation of the peptide E.2 with the peptide of P.3.

3. Deprotection of the peptides obtained in (1) and The peptides are dissolved in 90% TFA and stirred for 1 hour at room temperature. The solvent is distilled off, and the residue taken up in water and lyophilised. After being dried over solid KOH, the residue is dissolved in tBu/Wa (lzl); Dowex X 8 in the acetate form is added, after which the mixture is stirred for about 1.5 hours. Then the ionexchanger is filtered off and the filtrate is lyophilised.

Obtained the acetates of:

Rf in BucPyzAczWa (2:3/41l/41l) on SiO EXAMPLE lV Preparation of AGluHisPhe-Arg- Phederivatives 1.17 g of BocMetGlu(OtBu)l-lisN l-l (A2) are dissolved in ml of DMF. This solution is cooled down, after which 3 ml of 2 N HCI in THF are added at 0C and 0.27 ml of isoamyl nitrite at 20C and the mixture is stirred for 7 minutes.

Then 1.58 g of the peptide HPhe-Arg- Phe-Ol-l.acetate (N.4.4) are added, and the pH is adjusted to 7 with TAA.

Then the mixture is stirred for 70 hours at 0C, after which the solvent is evaporated in vacuum and the residue taken up in ethyl acetate and washed with water. The organic layer is evaporated to dryness and the residue recrystallised from ethylacetate (Rf in BzzEtOl-l (8:2) 0.20).

Lb. BocMetGlu(OtBu)-HisPhe-Arg-- Phe-derivatives 16 By condensation of BocMetGlu(Ot- Bu)-l-lisN H (A2) with HPhe-ArgPhe-NH (N.4.2); HPhe-Arg- PheN(CH (N.4.3) or HPheArg-PheOMe (N.4.l) by the process described in (a) are obtained:

(Rf in BzzEtOH 8:2).

l.c. BocAGlu(OtBu)HisPhe-Arg- Phe-OH (A Val or Ala) By condensation of BocValGlu(Ot- Bu)HisN H (C.2) or BocAlaGlu(Ot- Bu)HisN H (F.l) with H-PheArgPhe-OH (N.4.4) by the process described above are obtained:

BocAlaGlu(OtBu)His-PheArg-- Phe-OH.

l.d. DesaminoMetGlu(OtBu)HisPhe-Arg-PheOH Condensation of Desamino-Met-Glu(0t- Bu)HisN l-l (F.3) with HPheArgPheOH (N.4.4) by the azide method described in 21), yields the protected peptide: DesaminoMetGlu(Ot- Bu)His-PheArg-PheOH.

2. Removal of protecting group(s) Of the peptides prepared in (l) 250 mg are dissolved in 10 ml of trifluoro acetic acid and stirred for 1 hour at 20C. The solvent is distilled off, after which the residue is taken up in water and lyophilised. After being dried over solid potassium hydroxide, the residue is dissolved in t-butanol/water (1:1) and the solution stirred with Dowex X 8 in the acetate form to exchange the trifluoro acetate for acetate. When the pH of the solution has become 4 or 5, the ionexchanger is filtered off and the filtrate lyophilised. After counter current distribution the acetates are obtained of:

EXAMPLE V Synthesis of A-GluHisPheLysPhederivatives l.a. BocD-MetGlu(OtBu)His-PheLys(- Boc)Phe derivatives.

1.17 g of BocDMet-Glu(OtBu)HisN H (8.2) are dissolved in 20 ml of DMF. The solution is cooled down. after which 3 ml of 2 N HCl in THF are added at 0C and 0.27 ml of isoamyl nitrite at 20C, after which the mixture is stirred for 7 minutes. After that 3 mmol of the peptide prepared in M.2, M.3, MA or M.5 (H-PheLys(Boc)Phe-derivatives) are added and the pH is adjusted to 7.3 with TAA. After 17 70 hours stirring atC the solvent is distilled off in vacuum and theresidue taken up in ethyl acetate and washed with water. Then the organic layer is evaporated to dryness. The residue is pure enough for further processing. Obtained in this manner:

l.b. By using the peptide Boc-B-Ala-Glu(0t- Bu)-l-lis-N H (D.2)' instead of BocDMet- Glu(OtBu)-His-N H is obtained:

l.c. By using the peptide derivative Desamino-Met- -Glu(OtBu)l-lis-N H (F.3) instead of described in (a) the following peptides are obtained:

Desamino-MetGlu(OtBu)HisPhe-Lys(- Boc)-PheOH DesaminoMet-Glu(OtBu)-His-Phe-Lys(- Boc)-PheOMe DesaminoMet-Glu(OtBu)His-Phe-Lys(- Boc)PheNH DesaminoMet-Glu(OtBu)HisPhe-Lys(- EXAMPLE VI x Synthesis of A-Glit-Hls-Phe-Lys-phenylaikyl amides (X f or NH1) By the process, described in example I.a, one of the peptide hydrazides preparedin A- G is converted into the azide and condensed with H-Phe-Lys(Boc)PPA (K.4), HPhe-Lys(Boc- )Amf. (L.l HPheLys(Boc)-PEA (L2) or H-Phe.--Lys(B 0c)-HPEA (L3).

Deprotection of the peptides obtained in: this manner with TFA 90%, followed by-exchange for acetate by means of Dowex X 8 in the acetateform, yields the acetate of the following peptide derivatives:

EXAMPLE Vll Sulfoxides 1. Of the peptide HMetGlu-HisPheArg-- Phe-OH (Ex. lV.2) 45 mg are dissolved in 4 ml of acetic acid, after which l5 ml of 30% H 0 are added. The mixture is stirred for l hour at about 20C, after which a suspension of 20 mg of platinum black in 2.5 ml of glacial acetic acid is added and stirring is continued for 30 minutes. Then the mixture is filtered and the filtrate evaporated to dryness in vacuum. The residue is taken up in 10 ml of t.butanol/water and lyophilised.

Rf of the peptide obtained: H-Met O)- Glu-His-Phe-Arg-Phe-OH in Bu:Py:Ac:Wa (4:3/4zl/4zl) 0.20 on SiO 2. In the same manner the following peptidesulfoxides are obtained:

Rl 0.36 Rf 0.28

1. Of the peptide H-D-Met-Glu-Hos-Phe-Lys-Phe- OH (example V.2) mg are dissolved in a mixture of 0.5 ml of water, 0.1 ml of4 N perchloric acid, 0.02 ml of0.5 M ammonium molybdate, after which 0.06 ml of 30% H 0 is added.

The mixture is stirred for 2 hours at a temperature of about 10C, after which Dowex X 8 in the acetate form is added. After 30 minutes stirring the ionexchanger is filtered off and the filtrate lyophilised.

Rf in BuzAczWa (4:1:1) of the peptide: H-D-Met O )-Glu-His-PheLys-lPhe-OH is 0.22 on SiO 2. In the same manner the following sulfones are pre pared:

} 19 EXAMPLE lX Zinc complexes Of a solution of zinc chloride containing 50 mg of zinc per ml, 1.5 ml are added to a solution of 31.5 mg of Na i-W 2 H O in 30 ml of distilled water. The precipitate of zinc phosphate formed during this addition is dissolved by adding 4 N HCl. Then 175 mg of NaCl and 0.5 g of benzyl alcohol are added to this mixture, after which 150 mg of the hexapeptide HLMet-- L-GluLHisL-PheLLys-LPheOl-l are dissolved in this mixture. Then enough 1 N sodium hydroxide is added to obtain a pH of 8.5, after which the volume is completed with distilled water to 50 ml. 1 ml suspension contains:

Owe-u EXAMPLE X Preparation of H-Met (1, O)GluHis- PheArgPheOH BocLMet (1 O)OH is prepared by reacting Boc-azide with H-L-Met (l,- O)OH, described in J. Biol. Chem. 169, 477 (1947). BocLMet(- 1, O)OH: m.p. 68C; [11],, =58 (c =1, DMF). This N-protected amino acid is converted into the corresponding N-hydroxy-succinimido ester by treatment with DCCI and HOSu. The active ester obtained is used at once for a coupling reaction with H--Glu(Ot- Bu)His-Phe--ArgPhe Ol-l (obtained by the condensation of Z-Glu(OtBu)His-azide with H- PheArgPhe-OH, followed by hydrogenation of the Z-moiety) in the presence of N-ethylmorpholine.

The resulting peptide derivative: BocL-Met(- 1, O)-Glu(OtBu)-HisPhe-ArgPhe-OH, Rf in Bz:EtQH 8; 2) -0.1 8 on $102, 18 deprotected in the manner described before by means of TFA and converted into the acetate. H-L--Met(1,- O)Glu-- His- Phe-ArgPhe-OH.acetate:

Rf in BuzPyzAczWa (4:3/4:l/4:1) 0.28.

In the same manner the peptide-sulfoxide:

20 H-LMet(d, O)Glu-His-Phe-Arg- PheOH.acetate is prepared starting from BocL- Met(d, O)-OH, mp. C.

What is claimed is: 1. A peptide of the formula:

in which A is selected from the group consisting of HL-Met, H-D-Met, HLMet O), H-- D-Met O), HLMet 0 H-DMet 0 desamino-Met, desamino Met( O), desamino-Met 0 and the moeity: H N-BCO, in which B is alkylene having 16 carbon atoms,

X is selected from the group consisting of OH and L Q is selected from the group consisting of L-Arg and L-Lys, and Y is selected from the group consisting of LPhe--OH. LPheG|yOH, and (N-phenyl'alkyl) amino of the formula in which ALK is alkylene with 1-6 carbon atoms and R is selected from the group consisting of hydrogen and hydroxy, and functional derivatives of said peptide selected from the group consisting of pharmaceutically acceptable acid addition salts, derivatives in which one or more free amino groups are substituted by acyl derived from an aliphatic carboxylic acid with 16 carbon atoms, unsubstituted amides or lower alkyl (1-6 C) substituted amides of those peptides having a free carboxyl group, esters derived from aliphatic or araliphatic alcohols with l-l8 carbon atoms, and metal complexes thereof.

2. A peptide according to claim 1 of the formula:

in which A, X and 0 have the meanings indicated in claim 1.

3. A peptide according to claim 1 in which A is selected from B-Ala, Desamino-Met, DMet, and the sulfoxide and sulfone of L-Met, D-Met and Desami no-Met.

4. Metal complexes of the peptides and peptide derivatives as claimed in claim 3. 

1. A PEPTIDE OF THE FORMULA: A-L-G;I(X)-L-HIS-L-PHE-Q-Y IN WHICH A IS SELECTED FROM THE GROUP CONSISTING OF H-LMET, H-D-MET, H-L-MET(>O),, H-D-MET(>O), H-L-MET(>O2), H-D-MET(>O2), DESAMINO-MET, DESAMINO-MET(>O), DESAMINO-MET(>O2), AND THE MOEITY: H2N-B-CO, IN WHICH B IS ALKYLENE HAVING 1-6 CARBON ATOMS, X IS SELECTED FROM THE GROUP CONSISTING OF OH AND NH2, Q IS SELECTED FROM THE GROUP CONSISTING OF L-ARG AND L-LYS, AND Y IS SELECTED FROM THE GROUP CONSISTING OF L-PHE:OH,L-PHE:GLY-OH, AND (N-PHENYL-ALKYL) AMINO OF THE FORMULA
 2. A peptide according to claim 1 of the formula: A-L-Glu(X)-L-His-L-Phe-Q-L-Phe-OH in which A, X and Q have the meanings indicated in claim
 1. 3. A peptide according to claim 1 in which A is selected from Beta -Ala, Desamino-Met, D-Met, and the sulfoxide and sulfone of L-Met, D-Met and Desamino-Met.
 4. Metal complexes of the peptides and peptide derivatives as claimed in claim
 3. 